Ultrasound contrast agent dosage formulation

Abstract

Clinical studies have been conducted and specific dosage formulations developed using polymeric microparticles having incorporated therein perfluorocarbon gases that provide significantly enhanced images of long duration. The dosage formulation includes microparticles formed of a biocompatible polymer, preferably including a lipid incorporated therein, and containing a perfluorocarbon that is a gas at body temperature. The microparticles are provided to a patient in an amount effective to enhance ultrasound imaging in the ventricular chambers for more than 5 minutes or in the mycocardium for more than a minute, in a dose ranging from 0.025 to 8.0 mg microparticles/kg body weight. Preferably the dose ranges from 0.05 to 4.0 mg microparticles/kg body weight. The dosage formulation typically is provided in a vial. A typical formulation is in the form of a dry powder that is reconstituted with sterile water prior to use by adding the water to the vial or syringe of the dry powder and shaking to yield an isosmotic or isotonic suspension of microparticles.

We claim: 
     
       1. A dosage formulation of a dry powder which is reconstituted with a pharmaceutically acceptable carrier for use as an injectable enhanced ultrasound contrast imaging agent, wherein the dosage formulation comprises
 (a) a container of a defined size for the dry powder, 
 (b) the dry powder comprising an amount selected from the group consisting of 150-250 mg and 250-1000 mg of dry powdered microspheres comprising a poly(hydroxy acid), copolymer or blend thereof and a hydrophobic compound, wherein the microspheres are porous spheres with a honeycombed structure or sponge-like structure, wherein the microspheres have a mean size ranging from 1.8 to 3.0 microns, and 
 (c) n-perfluorobutane (C 4 F 10 ) gas, 
 wherein, upon reconstitution of the dry powder in the container by adding a defined amount of the pharmaceutically acceptable carrier suitable for injection, a suspension of microspheres having a concentration ranging from 1.5×10 9  to 2.8×10 9  microspheres/mL of suspension or a microsphere mass concentration ranging from 25 to 50 mg microspheres/mL suspension is formed, and 
 wherein the suspension of microspheres provides enhanced ultrasound images of the myocardium for more than one minute. 
 
     
     
       2. The dosage formulation of  claim 1  providing enhanced ultrasound images in the ventricular chambers for at least 30 minutes. 
     
     
       3. The dosage formulation of  claim 1 , comprising up to 4.0 mg microspheres/kg body weight for a 70 kg person. 
     
     
       4. The dosage formulation of  claim 1  comprising sterile water as the pharmaceutically acceptable carrier suitable for injection. 
     
     
       5. The dosage formulation of  claim 4  forming a suspension having a microsphere mass concentration ranging from 30 to 45 mg microspheres/mL suspension. 
     
     
       6. The dosage formulation of  claim 1 , wherein the microspheres have a mean particle size ranging from 1.9 to 2.6 microns. 
     
     
       7. The dosage formulation of  claim 1  comprising a dose ranging from 0.5 to 4.0 mg microspheres/kg body weight for a 70 kg person. 
     
     
       8. The dosage formulation of  claim 7  wherein the dose is selected from the group consisting of 0.5 mg microspheres/kg body weight, 2.0 mg microspheres/kg body weight and 4.0 mg microspheres/kg body weight for a 70 kg person. 
     
     
       9. The dosage formulation of  claim 1  wherein the n-perfluorobutane (C 4 F 10 ) is provided in an amount between 75 and 500 μg/mL of reconstituted microsphere suspension. 
     
     
       10. The dosage formulation of  claim 9  wherein the n-perfluorobutane (C 4 F 10 ) is provided in an amount between 100 and 400 μg/mL of reconstituted microsphere suspension. 
     
     
       11. The dosage formulation of  claim 10  wherein the n-perfluorobutane (C 4 F 10 ) is provided in an amount between 150 and 350 μg/mL of reconstituted microsphere suspension. 
     
     
       12. The dosage formulation of  claim 1 , wherein the hydrophobic compound is incorporated with the poly(hydroxy acid), or copolymer or blend thereof at a ratio of between 1 and 12% (weight hydrophobic compound/weight polymer). 
     
     
       13. The dosage formulation of  claim 12  wherein the hydrophobic compound is a lipid. 
     
     
       14. The dosage formulation of  claim 13  wherein the lipid is a phospholipid selected from the group consisting of dioleoylphosphatidylcholine (DOPC), dimyristoylphosphatidylcholine (DMPC), dipentadecanoylphosphatidylcholine (DPDPC), dilauroylphosphatidylcholine (DLPC), dipalmitoylphosphatidylcholine (DPPC), distearoylphosphatidylcholine (DSPC), diarachidoylphosphatidylcholine (DAPC), dibehenoylphosphatidylcholine (DBPC), ditricosanoylphosphatidylcholine (DTPC), dilignoceroylphatidylcholine (DLGPC),and phosphatidylethanolamines. 
     
     
       15. The dosage formulation of  claim 14 , wherein the poly(hydroxy acid) copolymer is poly (lactide-co-glycolide) with a lactide to glycolide ratio of 1:1 and a weight average molecular weight ranging from 20 to 40 kDa, and wherein the lipid is diarachidoylphosphatidylcholine incorporated with the polymer in a range of between 5 and 6.6% (weight lipid/weight poly(hydroxy acid) copolymer). 
     
     
       16. The dosage formulation of  claim 1  wherein the container is a vial or syringe. 
     
     
       17. The dosage formulation of  claim 16 , wherein the vial or syringe further comprises one or more excipients selected from the group consisting sugars, salts, and surfactants. 
     
     
       18. The dosage formulation of  claim 1  consisting essentially of one or two doses. 
     
     
       19. The dosage formulation of  claim 1  consisting essentially of up to five doses. 
     
     
       20. A kit for enhanced ultrasound contrast imaging comprising
 (i) an dry powder dosage formulation comprising
 (a) a container, 
 (b) an amount selected from the group consisting of 150-250 mg and 250-1000 mg of dry powdered microspheres comprising poly(hydroxy acid) or copolymer or blend thereof and a hydrophobic compound, 
 
 wherein the microspheres are porous spheres with a honeycombed structure or sponge-like structure, wherein the microspheres have a mean size ranging from 1.8 to 3.0 microns, and
 (c) n-perfluorobutane (C 4 F 10 ) gas, and 
 
 (ii) a pharmaceutically acceptable carrier solution suitable for injection for reconstituting the dosage formulation, 
 wherein, upon reconstitution of the dry powder dosage formulation in the container with the pharmaceutically acceptable carrier, a suspension of microspheres having a concentration ranging from 1.5×10 9  to 2.8×10 9  microspheres/mL of suspension or a microsphere mass concentration ranging from 25 to 50 mg microspheres/mL suspension is formed, 
 wherein the microspheres provide enhanced ultrasound images for more than one minute in the myocardium, when the microspheres are administered intravenously. 
 
     
     
       21. The kit of  claim 20 , wherein the container is a vial or syringe and wherein the kit further comprises a second vial or syringe of a defined amount of the pharmaceutically acceptable carrier for suspending the microspheres. 
     
     
       22. The kit of  claim 20 , wherein the pharmaceutically acceptable carrier is selected from the group consisting of water for injection, sterile water, saline, saline containing glycerol, saline containing TWEEN® 20, saline containing TWEEN® 80, isosmotic dextrose (5%), ½ isosmotic dextrose (2.5%), isosmotic mannitol (5%), ½ isosmotic mannitol (2.5%), isotonic mannitol containing TWEEN® 20 and isotonic mannitol containing TWEEN® 80. 
     
     
       23. The kit of  claim 22 , wherein the pharmaceutically acceptable carrier is water for injection. 
     
     
       24. The dosage formulation of  claim 1 , wherein upon reconstitution with the carrier the suspension of microspheres is in concentration suitable for intravenous administration as a bolus injection.